Rosenker, Christopher J
(2013)
Studies and Synthesis of Syringolin A, Functionalized Thiadiazines, and Thiol Additions to Enones.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Part one of this dissertation describes the formal synthesis of syringolin A. Syringolin A contains a unique 12-membered dipeptide core and has been shown to be a potent irreversible proteasome inhibitor. Completion of the formal synthesis of syringolin A was facilitated by the rapid access to non-proteinogenic α,β-unsaturated-γ-amino acid and α-amino acid fragments with complete stereochemical control utilizing the stereoselective addition of alkenylorganometallic reagents to chiral N-tert-butanesulfinylimines.
Part two discusses the development of a robust strategy for the preparation and selective functionalization of heterocyclic thiadiazines with four points of diversity. Hydrolysis of the pendant C-4 ester and functionalization of the resulting acid provided access to a small library of highly substituted thiadiazine analogues that exhibit favorable physicochemical properties for drug-like compounds.
Part three describes the investigation of the equilibria of thiophenol conjugate additions to enone-containing indole scaffolds. Our studies indicate that mono-β-substituted enones form thermodynamically favorable adducts with thiophenol. We also found that thiol eliminations to form enones are favorable in the presence of DBU but not Et3N. These experiments suggest that mono-β-substituted enones could be used as irreversible covalent protein modifiers.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
2 July 2013 |
| Date Type: |
Publication |
| Defense Date: |
10 December 2012 |
| Approval Date: |
2 July 2013 |
| Submission Date: |
13 December 2012 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
196 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Dietrich School of Arts and Sciences > Chemistry |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Syringolin
Total Synthesis
Heterocycles
Thiadiazine
Thiol conjugate addition
Enone addition equilibrium |
| Date Deposited: |
02 Jul 2013 14:39 |
| Last Modified: |
15 Nov 2016 14:08 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/16975 |
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